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Compositions comprising trimetrexate and methods of their synthesis and use

Inactive Publication Date: 2001-07-10
MEDIMMUNE ONCOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The trimetrexate compositions of the invention have unexpectedly been found to have improved chemical and physical characteristics as compared to prior trimetrexate compositions. For example, the trimetrexate compositions of this invention evidence little color change and resist degradation when stored over time. Solid trimetrexate compositions of the invention are also highly soluble in aqueous solvents, and may thus be readily reconstituted to form liquid trimetrexate compositions that arc free of solid precipitates and are suitable for parenteral administration to patients. The invention thus contributes significantly to the trimetrexate art by providing pharmaceutical products which fully exploit the biological activity of trimetrexate.
A sixth embodiment of the invention encompasses a method of increasing the stability of trimetrexate. According to this method, trimetrexate is contacted with ascorbic acid in a trimetrexate-to-ascorbic acid molar ratio of from about 1:0.1 to about 1:10, more preferably from about 1:1 to about 1:5, and most preferably from about 1:2 to about 1:3. The resulting composition may comprise trimetrexate ascorbate and / or trimetrexate and ascorbic acid. This method advantageously increases the stability of trimetrexate whether or not it is exposed to oxygen. Consequently, compositions of the invention need not be isolated from oxygen in order to be stable over long periods of time. Isolation from oxygen can, however, ensure the long term stability of some trimetrexate compositions. Thus one method of encompassed by this embodiment further comprises minimizing the exposure of a trimetrexate composition to oxygen. This is preferably done by storing the composition in a sealed container filled with an inert gas such as N.sub.2 or Ar. This may also be done by storing the composition in a sealed container from which air or other gasses have been removed (e.g., vacuum packing).

Problems solved by technology

Inhibition of DHFR results in the depletion of this coenzyme, and thus inhibits folate-dependent formyltransferases and interferes with thymidylate and purine biosynthesis.
The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

Method used

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  • Compositions comprising trimetrexate and methods of their synthesis and use

Examples

Experimental program
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example 1

Synthesis of Trimetrexate Ascorbate

Trimetrexate ascorbate may be prepared from trimetrexate free base, an adduct of trimetrexate such as the DMF adduct, or a trimetrexate salt such as trimetrexate hydrochloride or trimetrexate trifluoroacetate. As described above, the synthesis of these forms of trimetrexate is well known. A preferred method of preparing trimetrexate ascorbate from trimetrexate hydrate follows.

A. Trimetrexate Trifluoroacetate

To a suspension of 5 g of trimetrexate hydrate in 30 ml of 2-propanol and 15 ml of water was added 2.10 g of trifluoroacetic acid (approximately a 40% excess). The solid partly dissolved, but new crystals came out before it was completely gone. The mixture was heated to near reflux to give a clear dark yellow-green solution. To this was added 100 ml of 2-propanol. The product crystallized rapidly, and was collected after ice-cooling for 1 hour, washed with ice-cold 2-propanol and dried in air at 50% relative humidity to give 5.95 g of greenish-y...

example 2

Stability Measurement Protocol

High performance liquid chromatography (HPLC) was used to determine the purity and decomposition of trimetrexate in the compositions of the invention.

The HPLC mobile phase is prepared by first dissolving 5 g of sodium dodecyl sulfate (Aldrich 86,201-0 or equivalent) in 1100 ml water and adjusting the pH to 3.0 with glacial acetic acid (about 5 ml). 825 ml of HPLC grade acetonitrile is then added, and the solution is mixed thoroughly while avoiding excessive foaming. The unfiltered solution is then degassed by sonicating for 5 minutes. The solution is degassed immediately before use and at the beginning of each day.

Duplicate standard solutions are prepared with a trimetrexate ("TMTX") reference compound at a concentration of 0.2 mg / ml in the mobile phase solution ("STD-1" and "STD-2"). The standard solutions are stored under refrigeration when not in use, and fresh solutions are prepared daily. The system is checked before testing the sample solutions by...

example 3

Preparation of Liquid Dosage Form

Liquid dosage forms comprising trimetrexate and ascorbic acid, and liquid dosage forms comprising trimetrexate, ascorbic acid, and monothioglycerol, are made according to the procedures outlined below.

Liquid Dosage Form A (Trimetrexate and Ascorbic Acid).

A sufficient quantity of purified water is added to 12.5 grams of trimetrexate free base and 20 grams ascorbic acid to provide a mixture with a volume of 1000 ml. The mixture is stirred.

Liquid Dosage Form B (Trimetrexate, Ascorbic Acid, and 0.25% Monothioglycerol).

A sufficient quantity of purified water is added to 12.5 grams of trimetrexate free base, 20 grams ascorbic acid, and 2.5 grams monothioglycerol to provide a mixture with a volume of 1000 ml. The mixture is stirred.

Liquid Dosage Form C (Trimetrexate, Ascorbic Acid, and 0.50% Monothioglycerol).

A sufficient quantity of purified water is added to 12.5 grams of trimetrexate free base, 20 grams ascorbic acid, and 5 grams monothioglycerol to prov...

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Abstract

This invention is directed to the novel composition of matter trimetrexate ascorbate, to compositions comprising trimetrexate ascorbate, and to compositions comprising trimetrexate and ascorbic acid. These compositions are useful in the treatment of diseases in mammals such as, but not limited to, cancer, bacterial and protozoal infections, malaria, psoriasis, and rheumatoid arthritis. The invention is further related to methods of stabilizing trimetrexate to degradation caused by heat, light, oxygen, or water.

Description

1. FIELD OF INVENTIONThe invention relates to a novel composition of matter--trimetrexate ascorbate--and to methods of its preparation and use. The invention is further related to compositions comprising trimetrexate ascorbate, to compositions comprising trimetrexate and ascorbic acid, and to methods for preparing and using such compositions.2. BACKGROUND OF THE INVENTIONThe free base of trimetrexate, chemically named 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline, has the following structure: ##STR1##Trimetrexate is an inhibitor of dihydrofolate reductase (DHFR), an enzyme which catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, and thus inhibits folate-dependent formyltransferases and interferes with thymidylate and purine biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.Trimetrexate free base deco...

Claims

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Application Information

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IPC IPC(8): A61K9/19A61K47/20A61K47/12A61K31/517C07D239/00C07D239/95
CPCA61K9/0019A61K9/19C07D239/95A61K47/12A61K47/20A61K31/517Y02A50/30
Inventor STOGNIEW, MARTINZADEI, JAVAD M.
Owner MEDIMMUNE ONCOLOGY
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